Protease Inhibitors

HIV has proven an elusive and deadly adversary. For more than a decade, researchers and physicians have struggled to
develop potent new treatments to fight HIV and AIDS. Despite their efforts,
only a handful of drugs have been approved to treat HIV disease. Unfortunately,
these drugs have proved to be of limited usefulness, succeeding only in slowing
the inevitable progression to full-blown AIDS. Today, however, a new class of
drugs is providing fresh hope in our battle against the epidemic: protease
inhibitors.

Studies of protease inhibitors demonstrate that this new family of drugs
is vastly more potent than the first group of drugs used to treat HIV, reverse
transcriptase inhibitors (AZT, d4T, ddI, etc.). Data suggest that when used in
combination with approved antivirals such as 3TC plus AZT or ddI, protease
inhibitors can dramatically lower viral levels by as much as 99 percent in 60-to
90 percent of the individuals using the therapies. Though protease inhibitors
alone do not represent a cure for HIV infection or AIDS, they do provide renewed
hope for improved drug and treatment options for people with HIV and AIDS.

How Do Protease Inhibitors Work?

Much like reverse transcriptase inhibitors, protease inhibitors attack a viral
enzyme -- protease -- which plays a crucial role in HIV replication. This enzyme
serves as a biochemical scissor late in HIV replication by cutting longer chains
of proteins and enzymes in the host cell's nucleus into shorter pieces. Unlike
long chains, these shorter HIV proteins form new infectious HIV particles that
can infect neighboring cells.

Protease inhibitors are chemically similar to the long viral chain that
the HIV protease enzyme normally cuts. This process "gums up" HIV
protease enzymes that mistake the inhibitor for viral protein. As a result, the
longer HIV proteins remain uncut or miscut which causes them to produce
defective and therefore non-infectious new copies of HIV. Ultimately, protease
inhibitors can greatly reduce the number of new, infectious copies of HIV inside
the cells and curb the spread of HIV infection in the body.

Is There A Resistance Problem With Protease Inhibitors?

HIV's deadly ability to mutate and develop resistance to antiviral drugs
has proven the central barrier to our efforts to develop potent and lasting
therapies. Similar to all previous antiviral drugs, protease inhibitors can also
fall victim to HIV's uncanny ability to develop strains that are drug resistant.
However, at this time, the resistance is problematic only when the protease
drugs are administered in monotherapy.

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Another devastating threat posed by protease monotherapy is the
development of cross-resistance because resistance to one protease inhibitor
often confers multi-drug resistance to several of the other protease
inhibitors. However, with more carefully chosen treatment strategies in which
protease inhibitors are used in combination with approved antivirals such as 3TC
plus AZT or ddI, the size and duration of the antiviral effect is greatly
enhanced. Since combination therapy requires HIV to mutate its genetic
structure as many as eight times, it is hoped that the newly produced virus will
be much less viable.

The threat of viral resistance and cross-resistance to protease inhibitors
reiterates the importance of carefully delineated treatment plans. Without
carefully chosen and rigorously followed strategies, the potent effects of
protease inhibitors will be short-lived and quickly followed by multi-drug
cross-resistance.

The Crisis in Access to HIV Drug Therapies

Unfortunately, a large number of people living with HIV and AIDS will be
unable to access what has become the new "standard of care." Because
HIV disease is inevitably impoverishing for the great majority of people who
become infected, over the last 15 years a fragile and intricate AIDS care
infrastructure has been built to ensure that impoverished and medically needy
people with AIDS have access to basic health care and life-saving drugs. Today,
the myriad programs that make up this AIDS care infrastructure are threatened by
pressures on federal and state health budgets. The rise in price for basic
antiviral therapy -- which now runs from $3,000 for antiviral monotherapy to up
to $13,000 for combination therapy -- is likely to accelerate this alarming
process.

In 1994, fewer than 29 percent of people living with HIV were covered by
privately funded health insurance and that number is quickly decreasing. Of
those people who remain covered under some health insurance plan, a significant
number have insurance that either includes no coverage for prescription drugs or
caps prescription drug coverage either annually or over the life of the
policy.

Another 50 percent of people living with AIDS are covered by Medicaid.
Unfortunately, income caps for Medicaid average $434-per-month with many states
limiting patients to three prescriptions per month. Many other state Medicaid
programs include no drug coverage for "medically needy" people with
AIDS -- those who are allowed to "spend down" medical expenses to
qualify for Medicaid. And, now, the Medicaid program itself is under attack from
congressional proposals to block grant the program to the states with no
eligibility requirements -- meaning that people living with HIV and AIDS could
potentially be excluded -- and with a much-diminished amount of federal funding
-- a cut of up to 34 percent of federal Medicaid funding in some states.

For the tens of thousands of uninsured or underinsured people with HIV
disease who do not qualify for private health insurance or for Medicaid, the
only remaining options are state AIDS Drug Assistance Programs (ADAP) funded
under the Ryan White CARE Act, or indigent programs operated by the
pharmaceutical manufacturers. Unfortunately, long-term shortfalls in ADAP
funding have resulted in severe budget crises that caused at lease three states
to discontinue all formulary dispersals during 1995. Other states have canceled
planned expansion of formularies, established waiting lists for new clients,
restricted income eligibility levels, imposed strict new utilization controls,
or removed drugs from formularies. For example, the State of Illinois has
removed from its ADAP formulary 81 drugs to treat opportunistic infections in
order to pay for one protease inhibitor. The National Association of State and
Territorial AIDS Directors has estimated that these programs will need at least
$150 million in new funding if they are to maintain current service levels. No
one has yet estimated the cost of providing the new combination therapies to
these programs.

For all these reasons, we are becoming a country where people living with
HIV who have access to the resources necessary to afford
"state-of-the-art"
therapy will live longer and healthier lives than those who are dependent on
public programs or who are unqualified for those programs. It is the latter who
will die of a myriad of opportunistic infections -- dependent on emergency
rooms for their health care.

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